1-polyfluoroalkyl-1,4-benzodiazepin-2-thiones

ABSTRACT

7- CHLORO-1-(2.2,2-TRIFLUOROETHYL)-1,3-DIHYDRO-5-(2FLUOROPHENYL) -2H -1,4-BENZODIAZEPIN-2-THIONE AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.

United States Patent M 3,845,039 l-POLYFLUOROALKYL-1,4-BENZODIAZEPIN- Z-THIONES Martin Steinman, Livingston, N.J., assignor to Schering Corporation, Bloomfield, NJ.

No Drawing. Continuation-impart of application Ser. No.

220,370, Jan. 24, 1972, which is a continuation-inpart of application Ser. No. 62,164 Aug. 7, 1970 both now abandoned. This application July 26, 1972, Ser.

Int. Cl. C07d 53/06 U.S. Cl. 260-2393 D 2 Claims ABSTRACT OF THE DISCLOSURE Disclosed herein are l-polyfluoroalkyl-1,4-benzodia- Zepin-Z-thiones, a new class of chemical compounds particularly useful as sedatives, anti-anxiety agents and anticonvulsants.

wherein X is a member of the group consisting of chloro, bromo, trifiuoromethyl and nitro; Y and Z are independently selected from the group consisting of hydrogen, halogen, and trifluoromethyl; R is a poly-fluoro-lower alkyl group; R is hydrogen or a lower alkyl group; and the pharmaceutically acceptable salts thereof.

As used herein, the terms lower alkyl refer to both straight and branched-chain hydrocarbon radicals having up to six carbon atoms such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, cyclopropylmethyl and the like. The term halogen as used herein comprehends fluorine, chlorine, bromine and iodine. Chloro is the preferred X substituent. Preferably Z is hydrogen and Y is ortho-halo, with ortho-fluoro being especially preferred.

The term poly-fluoro-lower alkyl refers to lower alkyl radicals substituted with more than one fluoro radical and includes such moieties as trifluoromethyl, difluoromethyl, l,2,2,2-tetrafiuoroethyl, pentafluoroethyl, 2,2,3,3,3-pentafiuoropropyl, pentafluorocyclopropyl and the like. In the preferred embodiment of this invention, R; is trifluoromethyl, i.e. the 1-(2,2,2-trifluoroethyl) species. The preferred compound of this invention is 7-ch-loro-l-(2,2,2-trifluoroethyl)-l,3 dihydro (2 fluorophenyl) -2H-1,4 benzodiazepin-Z-thione.

3,845,039 Patented Oct. 29, 1974 The compounds may be used in the form of their therapeutically acceptable salts. Such salts include those formed in the conventional manner with both inorganic and organic acids such as hydrochloric acid, hydrobrornic, nitric acid, sulfuric acid, acetic acid, formic acid, succinic acid, maleic acid, p-toluenesulfonic acid and the like.

The compounds of formula I can be prepared by the reaction of the corresponding benzodiazepin-Z-one with a thiating agent such as phosphorus pentasulfide, which reaction can be depicted as follows:

R: F R N inert organic CHR1 P2S5 X solvent wherein X, Y, Z, R, and R have the above meaning. Suitable inert organic solvents include p-dioxane, pyridine, dimethylaniline, Tetralin, quinoline, the xylenes and the like.

The following examples illustrate the preparation of representative compounds of this invention.

EXAMPLE 1 Preparation of 7-chloro-1-(2,2,2-trifluoroethyl)-1,3- dihydro-S-phenyl-ZH-1,4-benzodiazepin-2-thione To a solution of 25.0 grams of 7-chloro-1-(2,2,2-trifluoroethyl)-1,3 dihydro 5 phenyl 2H-l,4-benzodiazepin-Z-one (0.071 mole) in 250 ml. of p-dioxane is added 17.31 grams of phosphorus pentasulfide (0.078 mole). The mixture is refluxed for 5 hours and then the solvent is remove-d under reduced pressure. The residue is diluted with methylene chloride and filtered through 375 grams of alumina; the same solvent is used for elution. The impure product thus obtained is then chromatographed on 1 kilogram of silica gel, using benzene as the eluent. The pure product is recrystallized from methylene chloride-cyclohexane and yields 8.73 grams of the title compound, m.p. 169-170 C.

EXAMPLE 2 Preparation of 7-ch1oro-l-(2,2,2-trifiuoroethyl)-1,3-dihydro-5-(2-fiuorophenyl)-2H-l,4-benzodiazepin-2-thione 7 Chloro 1 (2,2,2-trifluoroethyl)-l,3-dihydro-5-(2- fluorophenyl)-2H-1,4-benzodiazepin-2-one is substituted for the starting material in Example 1. This compound can be prepared by the oxidation of the corresponding 2,3-dihydrobenzodiazepine as described, for example, in my copending patent application Ser. No. 11,336. Suitable oxidizing agents include the metal oxides such as ruthenium tetraoxide and chromic trioxide.

To a solution of 1.8 grams 7-chloro-1,3-dihydro-5-ofluorophenyl-1-(2,2,2-trifluoroethyl)-2H-1,4 benzodiazepin-2-thione (0.005 mole) in 20 ml. of anhydrous p-dioxane is added 1.1 gram phosphorous pentasulfide (0.005 mole). The mixture is boiled under reflux for 4 hours with a calcium chloride drying tube to protect from atmospheric moisture. The solution is evaporated in vacuo. The residue is dissolved in methylene chloride and filtered through 200 grams of silica gel in a column. After concentration of the filtrate the residue is crystallized from methylene chloride-hexane and yield 1.2 grams of the title compound, m.p. 137.5 -139 C.

In a similar manner by substituting the corresponding l-polyfiuoroalkyl-1,4-benzodiazepin-2-one in the process of Example 1, one can prepare:

'l-Bromo- 1- (2,2,2-trifluoroethyl -1,3-dihydro-- (2- fluorophenyl 2H- 1 ,4-benzodiazepin-Z-thione 7-Nitro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2- fiuorophenyl -2H-1,4-benzodiazepin-2-thione '7-Chloro-1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2- chlorophenyl)-2H-1,4-benzodiazepin-2-thione 7 -Bromo-1- (pentafluorocyclopropyl) methyl 1,3 dihydro- 5-(2,6-difluorophenyl)-2H-1,4-benzodiazepin-Z-thione 7-Trifluoromethyl-1-(2,2-difiuoroethyl)-1,3-dihydro-5-(3- bromophenyl) -2H-1,4-benzodiaZepin-2-thione 7-Chloro- 1- 3 ,3,3-trifluoropropyl 1,3 dihydro-5- 3-trifluoromethylphenyl -2H-1,4-benzodiazepin-Z-thione 7-Bromo- 1- 2,2,3,3,3-pentafluoropropyl) -1 ,3-dihydro-3- methyl-5-(4-iodophenyl)-2H-1,4-benzodiazepin-2- thione.

The compounds of this invention exert such selective effects on the mammalian central nervous system as to be particularly useful as sedatives, anti-anxiety agents, and anticonvulsants. In pharmacological testing there has been observed significant differentials between those doses which elicit sedative, tranquilizing and anti-convulsant eifects and those doeses which cause neurological impairment (ataxia). Benzodiazepines currently suggested as sedatives do not appear to attain maximum levels of sedation. This may reflect a behavioral stimulant effect which occurs in at least some individuals and counteracts the sedation. The compounds of this invention tend to be free of this undesirable stimulant side effect.

Based upon standard laboratory investigative procedures such as the Antagonism of Pentylene Tetrazole, Everett and Richard, J. Pharm. and Exp. Ther., vol. 81, p. 402 1944) and Antagonism of Maximal Electro-Shock- Induced Seizures in Mice, Synward, E. A. et al., J. Pharm. and Exp. Ther., vol. 106, p. 319 (1952) for anti-convulsant activity; and Antagonism of Foot-Shock Induced Fighting in Mice, Tedeschi et al., J. Pharm. and Exp. Ther., vol. 125, p. 28 (1959) and Taming Activity in Monkeys, Randall, Diseases of the Nervous System, vol. 21, p. 7 (1960) for anti-anxiety activity; the Central Nervous System Activity and Acute Toxicity, Irwin, Science 136, p. 123 (1967) and squirrel monkey studies for sedative-hypnotic effects; it is indicated that when used as an anti-convulsant in man the dosage range is about 0.005 to 0.5 mg./ kg. of body weight per day, preferably orally administered in divided doses. Similarly, when used as anti-anxiety agent in man the dosage range of the subject compound is about 0.03 to 3 mg./kg. of body weight per day, preferably administered orally in divided dosages. In like manner, when used as a sedative in man the dosage range is about 0.06 to 2.5 mg./kg. of body weight preferably orally administered in a single dose.

The compounds of this invention may be administered alone or combined with other medicaments. In any event, a suitable pharmaceutically acceptable carrier is generally employed. A carrier is selected taking account of the intended route of administration, the physical properties of the compounds, and standard pharmaceutical practice. It should not react chemically with the compound to be administered. The compositions of this invention are preferably administered orally, athough parenteral administration is also contemplated. The preparations containing the active ingredients of this invention may be in the form of tablets, capsules, syrups, elixirs, suspensions and the like.

In the formulations of pharmaceutical preparations there can be employed such pharmaceutically acceptable diluenets, as for example, waeter, gelatin, lactose, starches, magnesium stearate, talc, vegetable oils and gums. The following examples show typical tablet and capsule formulations incorporating the preferred compound of this invention.

Tablet Formulations I. Formula and Method of Manufacture for 7-chloro- 1-(2,2,2-trifluoroethyl)-1,3-dihydro-5-(2 fiuorophenyl)- 2H-l,4-benzodiazepin-Z-thione.

Coated Tablets: Mg./core 7 Chloro-1-(2,2,2 trifluoroethyl)-1,3-dihydro-5- (2 fiuorophenyl) 2H 1,4-benzodiazepin-2- dihydro 5 (2 fluorophenyl)-2H-1,4-benzodiazepin-2- thione is mixed With the lactose, dicalcium phosphate, and sodium lauryl sulfate. The above mixture is screened through a No. 60 screen and granulated with an aqueous solution containing olyvinylpyrrolidone. Add additional water, if necessary, to bring powders to a pasty mass. Add corn starch and continue mixing until uniform granules are formed. Pass through a No. 10 screen, tray and dry in oven at C. for 12-14 hours. Reduce dried granulation through a N0. 16 screen, add sodium lauryl sulfate and magnesium sulfate, mix and compress into desired shape on a tablet machine.

Coating: The above cores are treated with a lacquer and dusted with talc to prevent moisture absorption. Sub-coat layers are added to round out the core. A sufficient number of lacquer coats are applied to make the core enteric. Additional sub-coats and smoothing coats are applied to completely round out and smooth the tablet. Color coats are applied until desired shade is obtained. After drying, the coated tablets are polished to give the tablets an even gloss.

II. Capsule Formulations:

Formula: Mg./capsule 7 Chloro 1-(2,2,2-trifluoroethyl)-1,3-dihydro- 5 (2-fluorophenyl)-2H-1,4-benzodiazepin-2- thione 4 Sodium Lauryl Sulfate 20 Lactose Magnesium Stearate 76 Procedure: Mix together 7-chloro-1-(2,2,2-trifluoroethyl) 1,3 dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-thione, sodium lauryl sulfate and lactose. Pass through a No. 80 screen. Add magnesium stearate, mix and encapsulate into the proper size two-piece gelatin capsule.

III. Suppository:

Formula: Mg./2 gs.

7 Chloro 1-(2,2,2trifluoroethyl)-l,3-dihydro-5- (2 fluorophenyl) 2H 1,4 benzodiazepin-Z- thione, micronized 8 Theobroma Oil, Pharm. Grade to make 2 gms.

Numerous variations of the above compositions of matter and processes for the manufacture will be apparent to one skilled in the art within the spirit of the present invention.

What is claimed is:

1. 7 chloro-l-(2.2,2-trifiuor0ethy1)-1,3-dihydro-5-(2- fiuorophenyl) 2H 1,4-benzodiazepin-2-thione and the pharmaceutically acceptable salts thereof.

2. 7 chloro l-(2,2,2-trifiuoroethyl)-1,3-dihydro-5-(2- fluorophenyl) -2H-l ,4-benzodiazepin-2-thione.

References Cited UNITED STATES PATENTS 2/1969 Toplissetal. 260--239.3 D

6 OTHER REFERENCES Sternbach et al.: Some Aspects of Structure-Activity Relationship in Psychotropic Agents of the 1,4-Benzodiazepine Series, A Symposium Held at the Regional Re- "i search Laboratory, Hyderabad, India, Csir New Delhi,

India (1966).

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. 01. X.R. 424-244 

